European Journal of Pharmaceutical Sciences 20 (2003) 341–346 Synthesis and anticonvulsant and neurotoxicity evaluation of N 4 -phthalimido phenyl (thio) semicarbazides P. Yogeeswari a,∗ , D. Sriram a , V. Saraswat a , J. Vaigunda Ragavendran a , M. Mohan Kumar a , S. Murugesan a , R. Thirumurugan a , J.P. Stables b a Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani 333031, India b Preclinical Pharmacology Section, Epilepsy Branch, National Institute of Health, MD 20892, USA Received 31 December 2002; received in revised form 22 July 2003; accepted 7 August 2003 Abstract The phenyl (thio) semicarbazide derivatives of phthalimido pharmacophore were synthesized and evaluated for their anticonvulsant and neurotoxic properties. Initial anticonvulsant screening was performed using intraperitoneal (i.p.), maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (sc STY)-induced seizure threshold tests in mice. Compound 2c afforded protection in all the three screens. Compounds except 1d, 2a and 2d showed no neurotoxicity up to 300 mg/kg. Compounds 1a, 1b, 2c, 2d, 2g and 2i were found to show oral MES activity. The compounds exhibited CNS depression and behavioral despair side effects, lesser than the conventional antiepileptic drugs. © 2003 Published by Elsevier B.V. Keywords: Phthalimides; Semicarbazides; Thiosemicarbazides; Anticonvulsants; CNS depressants 1. Introduction In recent years, aryl semicarbazones (Dimmock et al., 1993; Pandeya et al., 1999a, 2000; Puthucode et al., 1998) and thiosemicarbazones (Dimmock et al., 1990; Karali and Gursoy, 1994; Yogeeswari et al., 2002) have emerged as structurally novel anticonvulsants. Aryl semicarbazides are reported to display excellent anticonvulsant activity in mice and rats compared to that of phenytoin (Andurkar et al., 2001). The aryl semicarbazones were believed to interact at locations on the putative binding site designated as aryl binding site, a hydrogen bonding domain and an auxiliary aryl binding site (Dimmock et al., 1995a). The aryl binding site can be phenyl or other hydrophobic moieties with reten- tion of the anticonvulsant activity (Dimmock et al., 1995b; Pandeya et al., 2001). N-Phenyl phthalimide derivatives were also found to possess anticonvulsant potency associated with a phenytoin-like profile (Bailleux et al., 1994a, 1994b, 1995; Poupaert et al., 1995). More recently a variety of substituted ∗ Corresponding author. Tel.: +91-1596-244684; fax: +91-1596-244183. E-mail address: pyogie 2000@rediffmail.com (P. Yogeeswari). N-phenyl pthalimide derivatives have emerged as potent anti- convulsants (Vamecq et al., 1998, 2000). In view of these data, we have undertaken the synthe- sis and pharmacological evaluation of hybrids of aryl (thio) semicarbazides and N-phenyl phthalimides (Fig. 1). In the present work, synthesis of N 4 -phthalimido phenyl semicar- bazide and thiosemicarbazide derivatives was accomplished. The compounds were evaluated for their antiepileptic and neurotoxic properties through the antiepileptic drug devel- opment (ADD) program developed by the National Insti- tute of Health (Kupferberg and Stables, 1998; Stables and Kupferberg, 1997; White et al., 1995a, 1995b). The com- pounds were also evaluated for other CNS activities. 2. Experimental 2.1. Chemistry The melting points were determined in open capillary tubes in a Thomas Hoover melting point apparatus and are uncorrected. IR spectra were recorded as KBr pellets on a Jasco IR Report 100 Spectrophotometer. The 1 H NMR 0928-0987/$ – see front matter © 2003 Published by Elsevier B.V. doi:10.1016/j.ejps.2003.08.002